Side Effects

Glucose Intolerance, Insulin Sensitivity and "the Grim Reaper"

 Both starvation and rapamycin cause glucose intolerance. This is the opposite of glucose intolerance and insulin resistance seen in pre-diabetic persons characterized by overweight or obesity, high fasting insulin levels, high fasting glucose, decrease in insulin sensitivity and high mTOR. This is a very complicated subject and to understand it readers could look at "Koschei the immortal" and  Figure 2  "Insulin-resistance: two opposite conditions. Insulin resistance (IR) can be caused by the activation of mTOR and, paradoxically, by mTOR inhibition. In the first case, IR is detrimental for health, whereas in the second case, it is benevolent. The "x" axis is increasing mTOR activity. There is a U-shaped curve. The left side states  "Low mTOR, Pseudo-diabetes, slows Aging. The right side states, "High mTOR, diabetes type II, Fast aging." For further study, I suggest 2 references by Blagosklonny: 

"Rapamycin-induced glucose intolerance: hunger or starvation diabetes", 2011;

"Once again on rapamycin-induced insulin resistance and longevity: despite of or owing to", 2012.

None of this is actually very relevant  to intermittent use of rapamycin as an agent to slow aging. It is brought up because the most common argument against rapamycin is that it causes insulin resistance in high dose organ transplant use and Blagosklonny argues that is "benevolent IR" and related to starvation diabetes. This is a key discussion for daily use of rapamycin.

Intermittent use resembles caloric restriction and the following paper is most relevant: 

"Effects of long-term caloric restriction and endurance exercise on glucose tolerance, insulin action, and adipokine production", 2010, Fontana.

Fontana studied 28 volunteers who had been following severe (about 40%) caloric restriction for average of 7 years, 28 endurance runners (average 50 miles/week)and 28  sedentary controls eating Western diets. Average age 53, each group 24 men, 4 women. Following chart summarizes data:

                                          

                                         CR group                               Runners                          Controls

BMI                                      19.5                                       22.2                                 26.0 

Fasting glucose                   83                                          91                                    95 

Fasting insulin                     1.4                                         2.0                                   6.9 

Insulin sensitivity index    18.5                                        20.4                                 7.0 


On testing for glucose tolerance, 40% of CR group had glucose intolerance. 

The 17 in CR group with normal glucose tolerance had IGF-1 (insulin growth factor) of 205 (ng/mL) and the 11 in CR group in glucose intolerance had IGF-1 of 154 (ng/mL) p value 0.01.

In lifespan studies in worms (C. elegans) the DAF-2 gene encodes the IGF-1 gene for worms. Mutatations which knock out DAF-2 double the lifespan of the worms. Cynthia Kenyon, the leading expert, called the DAF-2 gene, "the grim reaper." This is IGF-1 the factor which was low in the CR group who demonstrated "glucose intolerance".

The study showed that "long-term caloric restriction is associated with impaired glucose tolerance in some individuals, presumably because of decreased insulin-mediated glucose disposal. This reduced glucose disposal is associated with lower circulating levels of IGF-1." And this is the very thing associated with increased life-span. 

I suggest that if we asked endocrinologists from Louisiana, the state with 36% obesity, they would say glucose intolerance is "pre-diabetic". On the other hand if we asked endocrinologists from South Sudan, where 42% of population is suffering from severe food shortage what glucose intolerance means, they would probably say, an indication of starvation.   

In the study noted above (Miller, Harrison, 2014) as they increased the dose of rapamycin in mice, they increased lifespan and as they increased lifespan they increased glucose intolerance. In mice, amount of lifespan increase and glucose intolerance were directly connected. Regardless of meaning of glucose intolerance in pre-diabetics;  glucose intolerance is a marker of the changes related to metabolism, which are part of extending lifespan. The controls had "normal" glucose tolerance and the mice with the 26% and 23% median lifespan extension were the mice with the "glucose intolerance". The facts from the research laboratory are that glucose intolerance and lifespan increase are both "abnormal" results which go together.                                                                                       

Old Wives' tale and Rapamycin

 The widespread use of rapamycin in clinical medicine to prevent diseases of aging is bedeviled by what I consider AN OLD WIVES' TALE. 


Rapamycin was introduced into clinical medicine about 20 years ago to be used as an immunosuppressant drug for organ transplant. Rapamycin as used for this purpose must inhibit both mTORC1 and mTORC2. This requires high continuous blood levels. Rapamycin has been used in over a million persons in transplant medicine. While long-term use is generally well tolerated, chronic DAILY rapamycin does cause too many side-effects for use in preventive medicine. 

In addition to side effects, daily rapamycin in humans as used in transplant medicine,  is not an anti-aging drug; but rather shortens life span.


Furthermore, there does not exist a scintilla of evidence that WEEKLY rapamycin or intermittent rapamycin, used  in moderate dose, NOT USED FOR IMMUNO-SUPPRESSION, causing unacceptable side-effects that would preclude its use to prevent age-related disease.

In above section, "It's the half life, stupid", I try to explain why daily rapamycin is bad; but weekly rapamycin is good, as regards use of rapamycin as anti-aging drug.

Intermittent rapamycin is used in a dose and schedule designed to lower mTORC1 and not significantly lower mTOR2.

While I fully agree that Rapamycin is a very potent medicine that should only be used under the care of a physician experienced in its use; nevertheless all the harmful side-effects caused by a high, daily immunosuppressive dose should not be ascribed to a non-immunosuppresssive dose and schedule of rapamycin.